While many might believe that the clash at the Loftus Versfeld stadium is crucial in the battle for second place behind the Germans, the group should be far closer than that with even the Aussies capable of shaking things up.
In tight groups any defeat can put a team under pressure and such a reverse in this game could see the losers potentially needing to beat Germany to reach the knock-out stages. It all suggests a tight and cagey affair for which neither side has had an ideal build-up.
Ghana have lost arguably their best player in Chelsea's Michael Essien, who misses the entire tournament with knee ligament damage, and that blow will certainly hit their hopes. What's more, their second most high-profile star, Inter Milan midfielder Sulley Muntari, is struggling to be fit for the opener following a thigh injury, although he expects to make it.
Despite the potential threat posed by Australia, Muntari believes that this match is the most important for the team's qualification. "Germany are the group favourites and so it will doubtless come down to Serbia - we don't know quite what to expect against them, but we know they are a good team," he said.
One advantage Ghana have is that they will know more about their opponents than vice versa, thanks to their Serbian coach Milovan Rajevic, who insists that he has no divided loyalties. "I am 100 per cent Ghanaian. I am a professional, my primary target is to win against Serbia and to qualify," he said.
Meanwhile, Serbia's preparations have been hit by a change of training venue due to a worry about picking up injuries. They switched from their practice pitch at the AW Muller Stadium in western Johannesburg to the University of Johannesburg's rugby stadium.
"I think they put a surface down a few days ago, so the pitch has not yet laid down nicely," said Lazio defender Aleksandar Kolarov, a reported target for new Real Madrid coach Jose Mourinho. "The surface was a bit unstable, so we were worrying about injuries."